Leukotriene B4 (LTB4) is one kind of arachidonic acid metabolites and one of the most potent activation substances of neutrophil and macrophage (see e.g., Samuelsson et al., “science”, (1987), vol. 237, pp. 1171-1176 and Shimizu et al., “Journal of Neurochemistory”, (1990), vol. 55, pp. 1-15). It is known that action of LTB4 on neutrophil or macrophage results in the induction of various responses important for biological defense, such as adhesion to vascular endothelial cells, degranulation of lysosome enzymes, production of active oxygen, chemotaxis into inflammatory tissues and the like. However, overproduction of LTB4 is deeply involved in the formation and aggravation of various diseases accompanied by inflammations or allergic responses, such as psoriasis (see e.g., Iversen et al., “Skin Pharmacology”, (1997), vol. 10, pp. 169-177), bronchial asthma (see e.g., Turner et al., “The Journal of Clinical Investigation”, (1996), vol. 97, pp. 381-387), rheumatoid arthritis (see e.g., Griffiths et al., “Proceedings of the National Academy of Science of the USA”, (1995), vol. 92, pp. 517-521), inflammatory bowel disease (see e.g., Sharon et al., “Gastroenterology”, (1984), vol. 86, pp. 453-460), ischemic renal failure (see e.g., Noiri et al., “Proceedings of the National Academy of Science of the USA”, (2000), vol. 97, pp. 823-828) and the like.
Therefore, the development of a therapeutic agent capable of selectively inhibiting the production or action of LTB4 in various ways has been desired for the prophylaxis or treatment of these diseases. In recent years, it has been clarified that LTB4 receptors include two kinds of receptors (BLT1, BLT2) having different expression distributions and affinities (see e.g., Yokomizo et al., “Nature”, (1997), vol. 387, pp. 620-624 and Yokomizo et al., “The Journal of the Experimental Medicine”, (2000), vol. 192, pp. 421-431). Therefore, expansion of the scope of LTB4 inhibitor selection has been desired more than ever.
For example, it has been reported that LTB4 receptor antagonists are useful for the treatment of patients with chronic rheumatoid arthritis (e.g., Alten et al., Annals of the Rheumatic Diseases, 2004, vol. 63, pp. 170-176). However, which of the two kinds of LTB4 receptors (BLT1, BLT2) the antagonist mainly acts on, and which receptor is mainly involved in chronic rheumatoid arthritis are not described.
Moreover, it is suggested that LTB4 stimulates the growth of cancer cells besides the above-mentioned diseases, and a report has documented that LTB4 receptor antagonists inhibited the growth of human pancreatic cancer, and induced the apoptosis of cancer cells (e.g., Tong et al., Clinical Cancer Research, 2002, vol. 8, pp. 3232-3242). However, which of the two kinds of LTB4 receptors (BLT1, BLT2) the antagonist mainly acts on, and which receptor is mainly involved in the growth of cancer are not described.
On the other hand, while benzofuran derivatives having a leukotriene inhibitory action have been disclosed (e.g., JP-A-61-17579, JP-A-5-202040 and JP-A-5-317024), the selectivity to LTB4 has not been disclosed.